Iron-overload disorders, including hereditary hemochromatosis, are typically insidious, causing progressive and sometimes irreversible end-organ injury before clinical symptoms develop. Iron overload in vital organs increases the risk for liver disease (cirrhosis, cancer), heart attack or heart failure, diabetes mellitus, osteoarthrtis, osteoporosis, metabolic syndrome, and other disorders. Iron overload can be inherited or acquired by receiving numerous blood transfusions or consuming high levels of supplemental iron. ?-Thalassemia and HFE-related hemochromatosis are two of the most frequently inherited disorders worldwide. Both disorders are characterized by low levels of hepcidin (HAMP), the hormone that regulates iron absorption. Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies or iron-chelating agents like deferoxamine. Most types of iron overload are associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Recently, hepcidin agonists have been reported to reduce serum iron levels in mice (Ganz, 2011a,b). However, hepcidin itself is problematic as a therapeutic because of difficulties in production and short plasma half-life. Recent studies have elucidated the role of matriptase-2 (Tmprss6) in the regulation of hepcidin expression. Transcriptional silencing of Tmprss6 (Guo, 2013; Schmidt, 2013) increased hepcidin expression, reduced iron levels in animals models of iron overload, and normalized key markers of erythropoiesis in a model of thalassemia. We propose to develop a best in class human monoclonal antibody ( humAb) inhibitor of Tmprss6. Targeting Tmprss6's proteolytic activity by systemic administration of an anti-Tmprss6 Ab may provide a greater degree of fine control than antisense or RNA-silencing based therapeutics designed to lower Tmprss6 expression, which have been problematic in the clinic Anti- Tmprss6 will be a more effective treatment for iron overload than current therapies or therapeutics based on antisense or RNAI inhibition of Tmprss6 expression, or hepcidin replacement. During this phase 1 project, we will identify and characterize an anti-Tmprss6 humAb as a best in class therapeutic to replace phlebotomy in HH patients and potentially reduce the need for transfusion in the thalassemia patients